WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis
Melanie Königshoff, … , Andreas Günther, Oliver Eickelberg
Melanie Königshoff, … , Andreas Günther, Oliver Eickelberg
Published March 16, 2009
Citation Information: J Clin Invest. 2009;119(4):772-787. https://doi.org/10.1172/JCI33950.
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WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by distorted lung architecture and loss of respiratory function. Enhanced (myo)fibroblast activation, ECM deposition, and alveolar epithelial type II (ATII) cell dysfunction contribute to IPF pathogenesis. However, the molecular pathways linking ATII cell dysfunction with the development of fibrosis are poorly understood. Here, we demonstrate, in a mouse model of pulmonary fibrosis, increased proliferation and altered expression of components of the WNT/β-catenin signaling pathway in ATII cells. Further analysis revealed that expression of WNT1-inducible signaling protein–1 (WISP1), which is encoded by a WNT target gene, was increased in ATII cells in both a mouse model of pulmonary fibrosis and patients with IPF. Treatment of mouse primary ATII cells with recombinant WISP1 led to increased proliferation and epithelial-mesenchymal transition (EMT), while treatment of mouse and human lung fibroblasts with recombinant WISP1 enhanced deposition of ECM components. In the mouse model of pulmonary fibrosis, neutralizing mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT. More importantly, these changes in gene expression were associated with marked attenuation of lung fibrosis, including decreased collagen deposition and improved lung function and survival. Our study thus identifies WISP1 as a key regulator of ATII cell hyperplasia and plasticity as well as a potential therapeutic target for attenuation of pulmonary fibrosis.

Authors

Melanie Königshoff, Monika Kramer, Nisha Balsara, Jochen Wilhelm, Oana Veronica Amarie, Andreas Jahn, Frank Rose, Ludger Fink, Werner Seeger, Liliana Schaefer, Andreas Günther, Oliver Eickelberg

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Figure 6

Increased WISP1 expression in ATII cells in vitro and in vivo in IPF.

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Increased WISP1 expression in ATII cells in vitro and in vivo in experim...
(A) mRNA levels of the CCN family members were analyzed by qRT-PCR using lung homogenates derived from donor or IPF lung explants (n = 10 each). (B) mRNA levels of WISP1 and CTGF were analyzed by qRT-PCR in microdissected septae from donor or IPF lungs (n = 5 each). Results in A and B are plotted as relative mRNA levels (ΔCt) and presented as mean ± SEM. (C) mRNA levels of WISP1 (white bars) and CTGF (black bars) were determined by qRT-PCR in primary human ATII cells (n = 4) or fibroblasts (n = 3) isolated from donor or IPF lung tissue. Results are plotted as log-fold increase (ΔΔCt) of mRNA levels in IPF-derived versus donor-derived cells and presented as mean ± SEM. (D) WISP1 protein expression in sections from control or IPF lung specimens was assessed by immunohistochemistry. Arrows indicate extracellular WISP1 staining. WISP1 and phospho–histone H3 (Phospho H3) protein expression in serial whole-lung sections from IPF patients was assessed by immunohistochemistry (bottom row). Data are representative of at least 2 independent experiments using at least 4 different lung tissues from IPF specimens. (E) WISP1 protein expression was determined in total protein lysates from donor or IPF lung tissue using Western blot analysis. Lamin A/C was used as a loading control. Data are representative of at least 2 independent experiments using 6 different lung tissues for donor and IPF specimens. (F) mRNA levels of WISP1 were analyzed by qRT-PCR using lung homogenates derived from IPF (n = 6), nonspecific interstitial pneumonia (NSIP; n = 4), or chronic obstructive pulmonary disease (COPD; n = 6) lung explants. Results are plotted as log-fold increase (ΔΔCt), compared with control lungs (transplant donor), and are presented as mean ± SEM. *P < 0.05, **P < 0.02.